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J. Biol. Chem., Vol. 280, Issue 22, 21418-21426, June 3, 2005

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Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice^*

Linan Chen, Barbara Cagniard, Tiffany Mathews, Sara Jones, Hyun Chul Koh¶, Yunmin Ding¶, Paul M. Carvey||, Zaodung Ling||, Un Jung Kang¶, and Xiaoxi Zhuang**

From the Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637, the Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the ^¶Department of Neurology, The University of Chicago, Chicago, Illinois 60637, and the ^||Department of Pharmacology, Rush University Medical Center, Chicago, Illinois 60612

Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and task-dependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month- and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.

Received for publication, December 13, 2004 , and in revised form, March 8, 2005.

^* This work was supported in part by the M. J. Fox Foundation (to X. Z.) and National Institutes of Health Grants NS43286 and NS32080 (to U. J. K.) and AA014091 (to S. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Neurobiology, Pharmacology and Physiology, The University of Chicago, 924 East 57th St., Chicago, IL 60637. Tel.: 773-834-9063; Fax: 773-834-3808; E-mail: xzhuang{at}bsd.uchicago.edu.

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